DESCRIPTION (Verbatim from applicant's abstract): The major objective of this application is to understand how retinal ganglion cells function by using electrophysiology and pharmacology to identify distinct ion currents that depolarize ganglion cells to action potential threshold; identify ion current properties that modulate repetitive action potential firing in these cells; and determine whether these properties are controlled over slow time-scales by cytoplasmic messengers. These experiments stem directly from measurements and calculations published during the previous funding period. The hypothesis that low-threshold Na+, Ca2+ and mixed-cation currents produce "non-synaptic excitatory potentials" in retinal ganglion cells will be tested by investigating whether low-threshold ion currents depolarize ganglion cells to action potential threshold, and whether they do so separately or sequentially. The hypothesis that slow changes in retinal ganglion cell excitability results from modulation of low-threshold ion currents by neurotransmitters will be tested by investigating whether modulatory neurotransmitters (dopamine) alter spike frequency by modulating the amplitude, gating kinetics, and/or voltage-sensitivity of Na+ currents, low-threshold Ca2+ currents and/or Ih currents. The last hypothesis, that mammalian retinal ganglion cells' excitability is influenced by low-threshold ion currents similar to those found in fish, will be tested by comparing the amplitude and kinetics of fish and mammalian ganglion cell ion currents, and by determining the ion currents responsible for the previous reports of voltage-rectification, and of tetrodotoxin-induced hyperpolarization in mammalian preparations. These experiments will be performed with whole-cell patch-clamp methods to voltage-clamp and current-clamp goldfish retinal ganglion cells. Recordings will be made from freshly dissociated ganglion cells and ganglion cells in retinal slices.